foreign [Music] a bit more how plasticity occurs in the short term let's explore the long-term aspect to do so we will consider an important area in the brain named the hippocampus that has been instrumental in the discovery and the development of synaptic plasticity to find the hippocampus we can take a coronal section at the level of the temporal lobe the hippocampus will be located in this external portion of the brain on either sides now the hippocampus is a very important region that mediates a lot of functions like memory and there is a lot of work done there to support this idea but for our purposes we will simply use the hippocampus to introduce some anatomical landmarks that will help us discuss plasticity Concepts that relate to the connections of the hippocampus and how it mediates memory are topics that will be covered in other videos now when it comes to the circuitry of the HEPA campus we must first note that it has three important regions with distinct cells the ca1 and ca3 regions which both have pyramidal neurons and the dentate region which has granule neurons the input to the hippocampus comes from what is known as the performant pathway which makes connections on granule cells as well as ca1 cells granule cells in the dentate region synapse to see it resells through the mossy fiber pathway and the C8 resells synapse on ca1 neurons through the Shaffer collateral pathway this completes the basic circuitry of the hippocampus I want to note that textbooks will often flip this diagram for some reason and most likely you have seen the hippocampus in this orientation but since we do not really consider the anatomical implications of the Epic campus I will use the unflipped orientation since it is more faithful to the coronal section in this circuit two general forms of long-term plasticity have been discovered long-term potentiation or ltp and long-term depression or LTD let's begin our discussion on long-term plasticity by first discussing ltp and what experiments allows us to see it for that we will consider the Shaffer collateral synapse of the ca3 neurons onto the ca1 neurons just so we said the anatomical basis the synapse between the ca3 and the ca1 neurons is mediated by glutamate and is thus excitatory it is important to note as well that this connection is formed on the dendritic spines of the ca1 neurons now the basic setup for plasticity experiments in such scenarios is to electrically stimulate the presynaptic cell and to record the response from the postsynaptic cell the epsp measurements measured at the postsynaptic cell are then plotted across time when electric stimulations are done at a low frequency let's say once or twice per minute the the amount of depolarization recorded on the postsynaptic cell is constant and passive you will notice that the epsp access is normalized to the Baseline and the Baseline corresponds to this first period when the cell is stimulated at low frequencies hence the first responses that we see here are at a hundred percent now when one induces a very high frequency trend of electrical stimulation in the presynaptic cell also known as a tetanus it causes the postsynaptic cell to fire after the tetanus period the size of the postsynaptic response when the neuron is stimulated again is bigger than what it was during the Baseline period as you can see the increase in response gets stabilized over time but the postsynaptic response remains bigger than Baseline a long time after the tetanus in such a plot we can compute the percent amount of plasticity that has been caused by the tetanus by this equation now that we understand how to interpret the basic plasticity recording plots let's see how we can understand the mechanisms that underlie ltp at the Sheffer collateral it turns out that ltp at the Schaefer collateral is highly dependent on nmda receptors if an NDA receptor seem foreign to you recall that they are ionotropic channels of glutamate that we've covered in our discussion on different neurotransmitters one important aspect that we have established in this discussion that can help us prove the relevance of nmdu receptors is that the compound ap5 acts as an antagonist to The nmda receptors hence when we perform tetonization experiments with ap5 blocking The nmda receptors there is no increase in postsynaptic response and thus entrust that nmda receptors play an important role in mediating ltp two Key properties of nmda receptors that make them such a unique receptor and explain how they can mediate plasticity is that first their opening requires glutamate binding and also post-synaptic depolarization to remove a magnesium blocker and second they are able to conduct calcium inside the cell when they open as we've seen time and time again in our discussion calcium is a very important second messenger in neurons if you recall the GQ pathway you will remember that sum of calcium's Downstream effects are The Binding to calmodulin and the activation of distinct kinases such as pkc and cam K2 the activation of these two kinases leads to two important aspects of plasticity first some of their Downstream phosphorylation targets are important proteins involved in the transport of ampa receptors in and out of the membrane accordingly the phosphorylation of these proteins causes ampa receptors to be moved from internal structures where they are stored to the membrane of the postsynaptic terminal with now more ionotropic ampa receptors the postsynaptic response is considerably increased as more inward current can enter the cell the second important Target for plasticity are The receptors themselves that can get phosphorylated this phosphorylation causes the channels to open more and let more current enter in this entire mechanism there is an important distinction to make between the induction and the expression of plasticity induction corresponds to the biochemical Cascade that is activated by the tetanus and the expression corresponds to the actual long-term changes so in this instance the addition of amporeceptors now this form of ltp that I have described lasts only a few hours and it has just been called early ltp however there are some forms of ltp called late ltp that can last even longer but they require a gene expression and protein synthesis to happen to get protein synthesis started in plasticity experiments remember from our discussions on kinases that kinases like PKA or map cake and phosphorylate transcription factors that can then go into the cell nucleus and start the synthesis of proteins one common example of such a transcription factor that is important in late ltp is crab which comes from the phosphorylation of PKA and map K to get this process started it turns out that the complex that calcium and calmodulin form can go on and activate a specific type of adrenal cyclase then this adenal cyclase causes the conversion of ATP to Camp which activates PKA PKA can then go on and activate map K and crab with sufficient protein synthesis in late ltp it can eventually lead to the formation of new synaptic contacts which again will increase the strength of the connection but now for larger time scales so days months or years now that we have a good idea of how ltp occurs at the Schaefer collateral I want to establish some properties that ltp at the synapse has because it is relevant in the grand scheme of the field of plasticity and memory first off I want to mention that when we measure the Baseline responses before the tetanus was applied these responses were sub threshold PSPs and they were not sufficiently strong to generate a change in synaptic strength to get the ltp to occur it is required that the presynaptic and postsynaptic partners both get very depolarized within a short amount of time in an experimental setting we can achieve this by stimulating the ca3 and ca1 neurons together when we consider a controlled pathway that is not stimulated along with the stimulated pathway we can notice that ltp only occurs at the site where both of the presynaptic and postsynaptic sites were stimulated this property is known as input specificity to explain input specificity we can think back to the nmda receptor mechanism indeed since the nmda receptor requires both The Binding of glutamate and a postsynaptic depolarization only the pathway where both of these requirements are met will cause ltp to occur now in more physiological settings the postsynaptic partner obviously does not get stimulated by an external electrode hence to achieve that postsynaptic depolarization that The nmda receptors need many Pathways need to cooperate together to reach that threshold this property of distinct Pathways to help each other out is referred to as cooperation tied to this idea of cooperation there was a very influential postulate written by Donald Hebb that said when an axon of cell a is near enough to excite SLB and repeatedly or persistently takes part in firing it some growth process or metabolic change takes place in one of both cells such that A's efficiency as one of the cells following B is increased basically what he is saying in this quote is that when a group of presynaptic cells that under owned cannot make the postsynaptic cell fire manage to make it fire then these connections should be strengthened accordingly this postulate is often coined as cells that fire together wired together from this postulate you will notice that the temporal ordering from pre to post is very important otherwise the connection will not be strengthened this leads to the idea of a coincidence between the pre and the postsynaptic cell which as we've seen is mediated by the nmda receptor along with cooperativity another fundamental property of ltp that can occur from the result of multiple Pathways interacting with each other is the concept of associativity associativity occurs in a similar fashion as cooperativity but an important distinction in nasos activity is that one of the pathways can make the postsynaptic partner fire the terminology to describe this Nuance is to refer to the pathway that can make the cell fire on its own as strong and the pathway that cannot make the cell fire on its own as weak hence in associativity there is a strong and a weak pathway but in cooperativity all the pathways are weak nonetheless the logic for associativity in terms of the nmda receptor will be similar to cooperativity the activity of the strong pathway allows to generate a sufficient amount of depolarization for the weak Pathway to open its nmda receptor and subsequently generate ltp there as well since we are on the topic I'll briefly mention that these Concepts such as cooperativity associativity and input specificity are key to understanding some fundamental aspects of memory which as I've mentioned are mediated by the airport campus so one way to think about cooperativity is that this property ensures that only the events that are really important will result in memory formation because there is a certain amount of threshold that they need to attain before the postsynaptic cell can fire when it comes to associativity if you're familiar with pavlovian conditioning you will recognize that the two concepts are similar to one another a strong unconditioned stimulus which is the strong pathway will be associated with the conditioned stimulus or weak Pathway to enhance the connection between the two lastly input specificity ensures that only specific memories are encoded and retrieved a final and important definition that I want to establish is the concept of homo synaptic plasticity and heterosynaptic plasticity if we consider two different Pathways interacting on a postsynaptic cell when one says that ltp is homosynaptic it means that it occurs at the synapse where the induction happened on the other hand etherosynaptic means that the change in response occurs at the synapse where induction did not happen so for example in the associativity scenario if we imagine that we only stimulate the strong pathway from its perspective there is going to be an x amount of homosynaptic plasticity from the perspective of the weak pathway there will be no heterosynaptic plasticity alright with these definitions now taken care of I want to address the aspect that ltp can occur through different mechanisms to do so let's consider the mossy fiber pathway between the granule neurons and ca3 neurons starting with the electrophysiological recordings it turns out that applying a tetanus to the synapse will also induce ltp however if we perform the recording with ap5 you will notice that the ltp still occurs it turns out that ltp and the mossy fiber pathway is entirely presynaptic and for that reason it does not require the activation of nmda receptors in this mechanism sustain depolarizations by the tetanus cause large amounts of calcium to enter the presynaptic terminal this calcium entry binds to calmodulin and activates a calcium Cal margin independent adenolol cyclase adenidal cyclase converts atps to cyclic amps which then go on to activate PKA PKA then goes on to phosphorylate other proteins involved in the vesicles cycle and that ends up increasing the transmitter release and the postsynaptic response now if we do the electrophysiological experiments with a PKA inhibitor you will see that the ltp note does not occur furthermore due to the fact that the postsynaptic cell is not engaged this form of ltp is said to be not associative alright now that we have seen ltp in great detail let's cover how long-term depression occurs to see LTD we can consider again the synapse between the ca3 neurons and the ca1 neurons in comparison to ltp that was induced by a very high frequency stimulation LTD arises from very low frequency stimulation of about 1 Hertz for 10 to 15 minutes and as you can see here the responses after induction now become lower relative to the Baseline the mechanism to induce ltp is actually very similar to that of ltp because both are mediated by calcium entry from nmda receptors however in LTD because the frequency of stimulation is so low small and slow Rises have calcium lead the calcium to activate phosphatases instead of Cam K2 remember that phosphatases are essentially the opposite of kinases and their activity mediates the removal of phosphate groups two important phosphatases that have been pointed out as being activated in such contexts are pp1 and calcinurin the activity of these two phosphatases eventually leads to the removal of Amper receptors that get internalized back into the endosome just like in late ltp there is also a late LTD that is mediated by protein synthesis now to finish our discussion on plasticity although the previous experiments that I have introduced in the hippocampus give us very good insights as to how plasticity is mediated it turns out that the induction Protocols are not very accurate as to what happens physiologically indeed trains have spikes in the hundreds of Hertz do not occur in the body but yet plasticity does happen a more physiological way to induce plasticity is Spike timing dependent plasticity or stdp in this Paradigm the induction is performed by pairing a presynaptic stimulus with the firing of an action potential in the postsynaptic Cell at a low frequency instead of the frequency of firing the main variable that we will focus on in stdp is the interval of time between the two stimuli generally speaking when the presynaptic stimuli precedes the postsynaptic stimuli it causes the connection to undergo ltp on the other hand if the presynaptic stimuli occurs after the postsynaptic stimuli it leads to LT D to illustrate this relation we can consider a plot of the time interval between the two signals and the generated response from this graph you will notice that for ltp and LCD to occur it is highly dependent on the time interval moreover the time interval is very small which means that plasticity can only get induced within a few tens of milliseconds when it comes to the mechanisms that underlie stdp they are again believed to be linked to The nmg receptors in a mechanism that is similar to what we have covered previously one thing that I will note right now that will be important for us to understand these mechanisms is that when an action potential is triggered in a neuron it turns out that it can actually back propagate throughout the neuron back to the dendrites so if we consider the ltp scenario first the pre-synaptic activity will cause the release of glutamate and the back propagating action potential will cause the required depolarization to kick out the magnesium and open the nmda receptors hence when the activity is pre before post The nmda receptors can fully open let calcium enter the cell and eventually lead to ltp in the LTD scenario because the glutamate arrives after the back propagating depolarization only a bit of calcium can enter the cell which leads to a long-term depression by the same mechanisms we have discussed based on what we covered previously you will notice that stdp follows the general principle of heb's postulate if the presynaptic cell contributes to the firing of the postsynaptic cell then the connection will be strengthened by ltp however the other side of this metal cannot be explained by heb's postulate the formal extension to help postulate came from Gunther's tent which basically said that the synaptic efficacy between the presynaptic and postsynaptic cell will be decreased by LTD if the presynaptic cell fails to contribute to the firing of the postsynaptic cell in the context of neuronal development we can interpret stdp as a simple mechanism that reinforces connections that make the postsynaptic cell fire and removes the connections that are irrelevant to its firing activity finally you will notice that there is an asymmetry in the intervals of time that cause ltp and LTD responses in hippocampal cells the interval for LTD is much longer than the interval for ltp and this is most likely explained by the fact that since there is a lot of noise the interval of LTD must be bigger to refine the connections and make sure that any unnecessary connection are removed all right with the basics of plasticity now covered we have essentially completed every point that I wanted to cover when it comes to the fundamentals of neurons [Music] thank you for watching this video if there was anything unclear or there was a mistake somewhere in the video make sure to let me know in the comment section if you enjoyed this video and found it useful you can consider leaving a like and subscribing to support the channel on the right you will see the informational resources that I've used to produce this video thank you again for watching and I'll see you in our next discussion [Music] [Music]